When treating cancer a combination of drugs targeting different disease-associated proteins or pathways is often needed to achieve the desired therapeutic effect. This project aims to develop a multitargeted ligand that can inhibit both X-linked inhibitor of apoptosis protein (XIAP) and insulin-like growth factor receptor type 1 (IGF-1R), proteins involved in inhibition of apoptosis and resistance development to anti-cancer therapies.[1,2] Multitargeted ligands offer the advantage of simultaneously modulating two, or more, different targets limiting the risk of side-effects to a single chemical entity, and poor patient compliance, which are both common in treatments with cocktails of drugs.[3] In this project we are using a fragment-based strategy, i.e. starting from a small chemical entity that binds to both targets. Compared to methods commonly used today, a fragment-based approach leaves more room for improvement during the optimization of multitargeted ligands. Our starting point is a quinone motif found in known inhibitors of XIAP (1) and IGF-1R (2).[1,2] Because of the potentially toxic redox system in this motif, we want to investigate the possibility to replace the quinone part for a fragment more suitable in drug development. A novel similarity search method, using molecular descriptors and multivariate methods, has been applied to create a virtual library of quinone-like fragments. These fragments have been evaluated in a docking study after which a representative set of fragments have been synthesized in 1-7 steps or acquired from commercial resources. The selected fragments will be tested for binding to XIAP and IGF-1R in a surface plasmon resonance assay. References [1] Nikolovska-Coleska, Z. et al., J. Med. Chem., 47, 2430-2440 (2004). [2] Stahl, P. et al., Angew. Chem. Int. Ed., 41, 1174-1178 (2002). [3] Morphy, R. et al., Drug Disc. Today, 9, 641-651 (2004).
Battling Cancer: A Fragment-Based Approach towards the Design of Multitargeted Ligands
Auzzas L
2010
Abstract
When treating cancer a combination of drugs targeting different disease-associated proteins or pathways is often needed to achieve the desired therapeutic effect. This project aims to develop a multitargeted ligand that can inhibit both X-linked inhibitor of apoptosis protein (XIAP) and insulin-like growth factor receptor type 1 (IGF-1R), proteins involved in inhibition of apoptosis and resistance development to anti-cancer therapies.[1,2] Multitargeted ligands offer the advantage of simultaneously modulating two, or more, different targets limiting the risk of side-effects to a single chemical entity, and poor patient compliance, which are both common in treatments with cocktails of drugs.[3] In this project we are using a fragment-based strategy, i.e. starting from a small chemical entity that binds to both targets. Compared to methods commonly used today, a fragment-based approach leaves more room for improvement during the optimization of multitargeted ligands. Our starting point is a quinone motif found in known inhibitors of XIAP (1) and IGF-1R (2).[1,2] Because of the potentially toxic redox system in this motif, we want to investigate the possibility to replace the quinone part for a fragment more suitable in drug development. A novel similarity search method, using molecular descriptors and multivariate methods, has been applied to create a virtual library of quinone-like fragments. These fragments have been evaluated in a docking study after which a representative set of fragments have been synthesized in 1-7 steps or acquired from commercial resources. The selected fragments will be tested for binding to XIAP and IGF-1R in a surface plasmon resonance assay. References [1] Nikolovska-Coleska, Z. et al., J. Med. Chem., 47, 2430-2440 (2004). [2] Stahl, P. et al., Angew. Chem. Int. Ed., 41, 1174-1178 (2002). [3] Morphy, R. et al., Drug Disc. Today, 9, 641-651 (2004).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
